KR0161237B1 - Process for preparing cyclopentene, cyclopentane and cyclohexane derivatives - Google Patents

Abstract

None.

Description

Method for preparing cyclopentene and cyclopentane derivatives

The present invention relates to certain cyclopentene derivatives having fungicidal activity and to methods of preparing certain cyclopentane and cyclohexane derivatives, all of which are useful in the preparation of other cyclopentane derivatives having fungicidal activity.

Bull. Chem. Soc. Jap., 43 (7), (1970), pp. 2204-8 describes 1-benzyl-2-carboxycyclopent-1-ene, Bull. Chem. Soc. Jap., 60 (2), (1987), pp. 836-8 discloses 1-benzyl-2-methoxycarbonylcyclopent-1ene. However, these documents do not indicate that any of these compounds exhibit fungicidal activity.

In addition, US Patent No. 4067823 describes 1-benzylidene-2-methoxycarbonylcyclopentane, and Liebigs Ann. Chem., (8), (1980), pp. 1283-95 describes 1- (4-methoxybenzylidene) -2-methoxycarbonylcyclopentane.

Therefore, co-pending patent application T616 describes compounds of the general formula (I) having fungicidal activity.

Wherein n represents an integer of 0-5, each R represents a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl , Carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, cycloalkyl or phenyl group, R ¹ and R ² independently represent a hydrogen atom or an alkyl group, R ⁵ Represents a hydrogen atom or an alkyl group or a cycloalkyl group, provided that when n is 0 and both R ¹ and R ² represent a hydrogen atom, R ⁵ does not represent a hydrogen atom or a methyl group.

The process for the preparation of the compounds of formula (I) described in T616 starting from commercially available starting materials requires at least five synthetic steps. Since the yield obtained in each step is not 100%, the potential yield of the compound of general formula (I) is reduced in each successive synthesis. However, the new process now finds a process for the preparation of the compound which consists of two fewer synthetic steps, providing a higher overall yield of the compound of general formula (I).

According to the present invention, in the presence of a polar solvent, a compound of formula (II) or (III)

Wherein n, R, R ¹ , R ² and R ⁵ are as defined above and X and Y independently represent a halogen atom, preferably a chlorine or bromine atom.

A process for preparing a compound of formula (I) as defined above is provided which consists of heating together with R ⁵ as defined above and M represents an alkali metal atom, preferably sodium atom.

Preferably, the polar solvent is a compound of formula (V)

Wherein R ⁵ is as defined above and is dimethylformamide or dimethyl sulfoxide.

If the compound of formula (V) is used as the solvent, preferably R ⁵ has the same meaning in formulas (IV) and (V). For example, if the compound of formula (IV) is sodium methoxide, the solvent of formula (V) is preferably methanol.

The reaction is conveniently carried out at 80 ° C. to the reflux temperature of the solvent. Excess formula (IV) compound is preferably used.

When either of the substituents R, R ¹ , R ² and R ⁵ represents or contains an alkyl substituent, it may be linear or branched, having up to 12, preferably up to 6, in particular up to 4 carbon atoms It may contain. Cycloalkyl substituents may contain 3-8, preferably 3-6, carbon atoms.

It is preferable that R ¹ and R ² independently represent a hydrogen atom or a C _1-4 alkyl group, especially a methyl group.

Preferably, R represents a halogen, in particular a chlorine atom.

It is also preferable that R ⁵ represents a hydrogen atom or a C _1-6 alkyl group.

It is particularly preferable that n is 1 and R preferably represents a chlorine atom substituted in the 4-position of the phenyl ring, both R ¹ and R ² represent a hydrogen atom or a methyl group, and R ⁵ represents a methyl group.

According to the present invention, compounds of the following general formula (II) are provided.

Wherein n represents an integer of 0-5, each R represents a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl , Carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, cycloalkyl or phenyl group, R ¹ and R ² independently represent a hydrogen atom or an alkyl group, R ⁵ Represents a hydrogen atom or an alkyl group or a haloalkyl group, provided that both R ¹ and R ² represent a hydrogen atom, and when R ⁵ represents a methyl group, n is not 0, and when n is 1, R represents a methoxy group Do not.

When any preceding substituent represents or contains an alkyl substituent, it may be linear or branched and may contain up to 12, preferably up to 6, in particular up to 4 carbon atoms.

It is preferable that R ¹ and R ² independently represent a hydrogen atom or a C _1-4 alkyl, in particular a methyl group.

Preferably, R represents a halogen, in particular a chlorine atom.

It is also preferable that R ⁵ represents a hydrogen atom or a C _1-6 alkyl group.

Particularly preferred sub-groups of compounds of formula (II) are those in which n is 1, R preferably represents a chlorine atom substituted in the 4-position of the phenyl ring, and both R ¹ and R ² are hydrogen It represents an atom or a methyl group, and R <^5> represents a methyl group.

The invention also relates to the presence of a solvent of the general formula (V)

(Wherein R ⁵ is as defined above)

Compound of formula (IV)

Wherein R ⁵ is as defined above and M represents an alkali metal, preferably sodium atom) and a compound of formula (III)

Wherein n, R, R ¹ , R ² are as defined above and X and Y independently represent a halogen atom, preferably a chlorine or bromine atom. Provided is a process for preparing the compound of II).

Preferably, R ⁵ has the same meaning in formulas (IV) and (V). For example, if it is a compound of general formula (IV) and sodium methoxide, it is preferable that the solvent of general formula (V) is methanol.

The reaction is conveniently carried out at 0 ° C. to room temperature using a slight excess of the compound of formula (IV).

According to another aspect of the invention there is provided a compound of formula (III).

Wherein n represents an integer of 0-5, each R represents a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonyl , Carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamino, cycloalkyl or phenyl group, R ¹ and R ² independently represent a hydrogen atom or an alkyl group, X and Y Independently represents a halogen atom.

When any of the above substituents represent or contain alkyl substituents, they may be linear or branched and may contain up to 12, preferably up to 6, in particular up to 4 carbon atoms. Cycloalkyl substituents may contain 3 to 8, preferably 3 to 6 carbon atoms.

It is preferable that R ¹ and R ² independently represent a hydrogen atom or C _1-4 alkyl, in particular a methyl group.

Preferably, R represents a halogen, in particular a chlorine atom.

It is also preferable that X and Y independently represent a chlorine or bromine atom.

Particularly preferred subgroups of compounds of formula (III) are those in which n is 1, R preferably represents a chlorine atom substituted in the 4-position of the phenyl ring, and both R ¹ and R ² represent a hydrogen atom or a methyl group And X and Y both represent a bromine atom.

The present invention also provides a process for the preparation of a compound of formula (III) as defined above comprising reacting compound XY (where X and Y are as defined above) with a compound of formula (IV) .

Wherein n, R, R ¹ and R ² are as defined above.

The method can be carried out in the presence of a solvent. Suitable solvents include petroleum, lower alcohols such as methanol, chlorinated hydrocarbons, eg carbon tetrachloride, ethers and acetic acid.

The reaction is suitably carried out at -10 ° C to room temperature, depending on the nature of the solvent, if a solvent is present. Preferable temperature is 0 degreeC-room temperature.

The compound of formula (VI) can be conveniently prepared by the reaction of a compound of formula (VII) and a compound of formula (VII) in the presence of a base.

Wherein R ¹ and R ² are as defined above.

Wherein n and R are as defined above.

Suitable bases include metal hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

The method is conveniently carried out in the presence of a solvent. Suitable solvents include water and lower alcohols.

The reaction is suitably carried out at 20 ° C.-100 ° C., depending on the nature of the solvent, if a solvent is present.

Compounds of formulas (IV), (V), (iii) and (iii) and compound XY are known compounds or can be prepared by methods analogous to known methods.

Compounds of formulas (I), (II) and (III) are useful as intermediates in the preparation of cyclopentane derivatives having fungicidal activity of the general formula (VII) below.

Wherein n, R, R ¹ and R ² are as defined above and A represents a nitrogen atom or a CH group. Certain compounds of formula IV are the subject of co-pending patent applications GB-A1-2180236 and EP-A2-0267778.

The compounds described in EP-A2-0267778 and GB-A1-2180236 exist in two stereoisomeric forms having the structure:

Letters A and B will be used later to refer to compounds having the same stereochemical configuration as isomers A and B above.

Isomers A and B can be separated, for example by chromatography, and exhibit different fungicidal activity. In general, the isomers of formula (VIIA) exhibit greater fungicidal activity than the isomers of formula (VIIB). The method used for synthesizing the compound of the general formula (VIIA) from the compounds of the general formulas (I), (II) and (III) is shown in the following scheme.

In this scheme, n, R, R ¹ , R ² , R ⁵ , X, Y and A are as defined above and R ³ is an optionally substituted alkyl or aryl group, preferably C _1-4 alkyl or Phenyl group, each of which is optionally a halogen atom, nitro, cyano, hydroxyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, _1-4 Alkylamino, di- _1-4 alkylamino, _1-4 alkoxycarbonyl, carboxyl, _1-4 alkanoyl, _1-4 alkylthio, _1-4 alkylsulfinyl, carbamoyl, _1-4 alkylamido Is substituted by one or more substituents selected from _C3-8 cycloalkyl and a phenyl group, Q represents hydrogen or an alkali metal, preferably a sodium atom. Intermediate compounds and method steps in this scheme that are not part of the present invention are the subject of co-pending patent applications T616, T622, T623 and T626.

The invention is further exemplified by the following examples.

Example 1

Preparation of 2-bromo-2- (α-bromo-4-chlorobenzyl) -5,5-dimethylcyclohexanone

(General Formula III; n = 1, R = 4-Cl, R ¹ = R ² = CH ₃ , X = Y = Br)

(a) Preparation of 2- (4-chlorobenzylidene) -5,5-dimethylcyclohexanone

A mixture of 3,3-dimethylcyclohexanone (34 g, 0.27 mole) and 4-chlorobenzaldehyde (38 g, 0.27 mole) in water (100 mL) containing sodium hydroxide (5.4 g, 0.27 mole) was refluxed for 24 hours. I was. Upon cooling, the mixture was extracted with toluene, flashed and crystallized from methanol to give 2- (4-chlorobenzylidene) -5,5-dimethylcyclohexanone (48 g).

Melting point: 85-86 ° C., yield; 75%

(b) Preparation of 2-bromo-2- (α-bromo-4-chlorobenzyl) -5,5-dimethylcyclohexanone

5 g (0.02 mol) of 2- (4-chlorobenzylidene) -5,5-dimethylcyclohexanone obtained in (a) was dissolved in dichloromethane (25 mL) and cooled to 5-10 ° C. Bromine (3.2 g, 0.02 mol) is added for 5 minutes, the resulting solution is flashed and triturated with methanol and then 5.5 g of 2-bromo-2- (α-bromo-4 as a white solid). -Chlorobenzyl) -5,5-dimethylcyclohexanone was obtained.

Melting point; 114-5 ° C., yield; 67%

Example 2

Preparation of 1- (4-chlorobenzylidene) -3,3-dimethyl-2-methoxycarbonylcyclopentane

(General Formula II; n = 1, R = 4-Cl, R ¹ = R ² = CH ₃ , R ⁵ = CH ₃ )

5 g (0.012 mol) of 2-bromo-2- (α-bromo-4-chlorobenzyl) -5,5-dimethylcyclohexanone obtained in Example 1 was dissolved in 7 ml of dichloromethane and the solution was It was added to 0.7 g (0.03 g atom) of sodium dissolved in methanol (50 mL) at 0-5 ° C. After another 10 minutes at 5 ° C., acetic acid (1.8 g, 0.03 mol) was added and the mixture was partitioned between petroleum and water. Working gave 3.25 g of crude product, which was found to contain 2.57 g of 1- (4-chlorobenzylidene) -3,3-dimethyl-2-methoxycarbonylcyclopentane by GC analysis. Yield 75%. The structure of the product was confirmed by NMR spectroscopy.

Example 3

Preparation of 1- (4-chlorobenzyl) -3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene

(Formula I; n = 1, R = 4-Cl, R ¹ = R ² = CH ₃ , R ⁵ = CH ₃ )

Crude 1- (4-chlorobenzyledene) -3,3-dimethyl-2-methoxycarbonylcyclopentane obtained in Example 2 was dissolved in methanol (20 ml) containing sodium (0.3 g) for 15 minutes. It was refluxed to obtain 1- (4-chlorobenzyl) -3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene as an oil.

Example 4

Preparation of 1- (4-chlorobenzyl) -3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene

(General Formula I; n-1, R = 4-Cl, R ¹ = R ² = CH ₃ , R ⁵ = CH ₃ )

(a) Preparation of 2-bromo-2- (α-bromo-4-chlorobenzyl) -5,5-dimethylcyclohexanone

10 g (0.04 mol) of 2- (4-chlorobenzylidene) -5,5-dimethylcyclohexanone prepared according to Example 1 (a) was dissolved in 50 mL of dichloromethane and cooled to 5-10 ° C. . Bromine (6.4 g, 0.04 mole) was added over 5 minutes to afford 2-bromo-2- (α-bromo-4-chlorobenzyl) -5,5-dimethylcyclohexanone in solution.

(b) Preparation of 1- (4-chlorobenzyl) -3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene

To the solution of 2.8 g (0.12 g atomic) sodium dissolved in 150 ml methanol was added the reaction mixture obtained in (a) at 5-10 ° C. for 15 minutes. After 20 minutes, the mixture was refluxed at 48 ° C. for 30 minutes. The solvent was flushed and the residue was partitioned between petroleum and water to give 11.4 g of crude product by evaporation which was 7.52 g of 1- (4-chlorobenzyl) -3,3-dimethyl- by GC analysis. It was found to contain 2-methoxycarbonylcyclopent-1-ene. Yield 67%. The structure of the product was confirmed by NMR spectroscopy.

Claims (6)

A process for producing a compound of formula (I), wherein the compound of formula (II) or formula (III) is heated together with the compound of formula (IV) in the presence of a polar solvent.

Wherein n represents an integer of 0-5, each R represents a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycar A carbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, cycloalkyl or phenyl group, R ¹ and R ² independently represent a hydrogen atom or an alkyl group, R ⁵ represents a hydrogen atom or an alkyl group or a cycloalkyl group, provided that when n is 0 and both R ¹ and R ² represent a hydrogen atom, R ⁵ does not represent a hydrogen atom or a methyl group, and X and Y independently represent a halogen atom And M represents an alkyl metal atom. The process for producing a compound of formula (I) according to claim 1, wherein the polar solvent is a compound of formula (V)

Wherein R ⁵ is as defined in claim 1. A process for producing a compound of formula (II), consisting of reacting a compound of formula (III) with a compound of formula (IV), in the presence of a solvent of formula (V).

Wherein n represents an integer of 0-5, each R represents a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycar A carbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, cycloalkyl or phenyl group, R ¹ and R ² independently represent a hydrogen atom or an alkyl group, R ⁵ represents a hydrogen atom or an alkyl group or a cycloalkyl group, provided that when R ¹ and R ² both represent a hydrogen atom and R ⁵ represents a methyl group, n is not 0, and when n is 1, R does not represent a methoxy group , X, Y and M are as defined in claim 1). The process for preparing a compound of formula (II), wherein R ⁵ has the same meaning in formula (IV) and formula (V). A compound of formula (III)

Wherein n represents an integer of 0-5, each R represents a halogen atom, nitro, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycar A carbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, cycloalkyl or phenyl group, R ¹ and R ² independently represent a hydrogen atom or an alkyl group or a cycloalkyl group Provided that when R ¹ and R ² both represent a hydrogen atom and R ⁵ represents an alkyl group of C _1-4 , n is not 0, and when n is 1, R does not represent a methoxy group, and X, Y and M Is as defined in claim 1). The process for preparing a compound of formula (I) according to claim 2, wherein R ⁵ has the same meaning in formulas (IV) and (V).